Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation

ABSTRACT

Methods for the treatment of CNS disorders using combinations of muscarinic activators and inhibitors, and medicaments comprising muscarinic activators and inhibitors.

FIELD OF INVENTION

The present invention relates to: 1) A method of using a combination ofone or more muscarinic agonists and one or more muscarinic antagonistsfor treatment of diseases that are ameliorated by activation ofmuscarinic receptors (e.g., schizophrenia and related disorders); 2) Amedicament comprising one or more muscarinic agonists and one or moremuscarinic antagonists.

BACKGROUND OF THE INVENTION

The acetylcholine neurotransmitter system plays a significant role in avariety of central nervous system (CNS) and peripheral functions.Acetylcholine signaling occurs through two different families ofreceptors: nicotinic receptors and muscarinic receptors. Muscariniccholinergic receptors are G-protein coupled receptors with fivedifferent receptor subtypes (M1-M5) (Raedler et al. American Journal ofPsychiatry. 160: 118. 2003), each of which are found in the CNS but havedifferent tissue distributions. Activation of the muscarinic systemthrough use of muscarinic agonists has been suggested to have thepotential to treat several diseases including Alzheimer's disease,Parkinson's disease, movement disorders and drug addiction. (U.S.2005/0085463; Langmead et al. Pharmacology & Experimental Therapeutics.117: 232:2008). Genetic evidence has suggested a direct link between themuscarinic system and both alcohol addiction (Luo X. Et al. Hum MolGenet. 14:2421. 2005) and nicotine addiction (Mobascher A et al. Am JMed Genet B Neuropsychiatr Genet. 5:684. 2010). M1 and M4 subtypes havebeen of particular interest as therapeutic targets for various diseases.For instance, the mood stabilizers lithium and valproic acid, which areused to treat bipolar depression, may exert their effects via themuscarinic system particularly through the M4 subtype receptor.(Bymaster & Felder. Mol Psychiatry. 7 Suppl 1:S57. 2002).

Some of the strongest linkages to the muscarinic system have been withschizophrenia, which is a serious mental illness affecting approximately0.5-1% of the population. (Arehart-Treichel. Psych News. 40:9. 2005).The disease is characterized by a set of symptoms that are generallydivided into three categories: 1) Positive symptoms (e.g.,hallucinations, delusional thoughts, etc.); 2) Negative symptoms (e.g.,social isolation, anhedonia, etc.); and 3) Cognitive symptoms (e.g.,inability to process information, poor working memory, etc.). (Schultz.Am Fam Physician. 75:1821. 2007). Patients who suffer from schizophreniaboth experience a major decline in quality of life and are at increasedrisk for mortality due to a number of factors, such as an increasedsuicide rate. (Brown et al. British Journal of Psychiatry. 177: 212.2000). The cost of schizophrenia to society is also significant assufferers of schizophrenia are much more likely to be incarcerated,homeless or unemployed.

Today, antipsychotics are the mainstay of treatment for schizophrenia.The first generation of antipsychotics are generally known as “typicalantipsychotics” while newer antipsychotics are generally called“atypical antipsychotics.” Both typical and atypical antipsychotics havelimited efficacy and severe side effects. There is little to nodifference in efficacy between typical and atypical antipsychotics, mostlikely due to the fact that both classes of drugs achieve theirtherapeutic effect through the same pharmacological mechanisms (e.g.,acting as dopamine receptor antagonists). (Nikam et al. Curr OpinInvestig Drugs. 9:37. 2008). Side effects of typical antipsychoticsinclude abnormal movement (e.g., rigidity) whereas atypicals havedifferent but equally significant side effects (e.g., major weight gain,cardiovascular effects, etc.). The side effect profile of currentantipsychotics further decreases compliance in a patient population thatis already frequently non-compliant. Thus, there exists a clear need fornew therapeutics to treat schizophrenia and related disorders (e.g.,schizoaffective disorder).

Clozapine is an example of an antipsychotic that has major side effects,including sialorrhea (hypersalivation) which occurs in up to 54% ofpatients. (Davydov and Botts, Ann Pharmacother. 34:662. 2000). The exactmechanism of hypersalivation remains unknown. (Rogers and Shramko.Pharmacotherapy. 20:109. 2000). Clozapine has a complex pharmacologicalprofile with appreciable activity at a variety of receptors, includingdopamine receptors, serotonin receptors, adrenergic receptors,muscarinic receptors and possibly others. (Coward. Br J PsychiatrySuppl. 17:5. 1992). Investigators have tried a variety ofpharmacological approaches in an attempt to counteract sialorrhea,including botulinum toxin (Kahl et al. Nervenarzt. 76:205. 2005) as wellas the antipsychotics amisulpride (Croissant et al. Pharmacopsychiatry.38:38. 2005) and sulpiride. (Kreinin et al. Isr J Psychiatry Relat Sci.42:61. 2005). Efforts have focused mostly on alpha2 adrenergic agonistsas well as anti-cholinergic drugs due to clozapine's known interactionwith these receptors. Anti-muscarinic drugs such as pirenzepine haveshown efficacy in small scale trials (Schneider et al.Pharmacopsychiatry. 37:43. 2004), but other trials with the same agentfound no effect. (Liu et at. J Clin Psychopharmacol. 21.:608. 2001).Alpha2 adrenergic agonist such as clonidine (Singh et al., JPsychopharmacol. 19:426. 2005) have also shown efficacy in reducingsialorrhea in small scale trials. However, Syed et al. reported in a2008 review that there is inadequate data to guide clinical practice.(Syed et al. Cochrane Database Syst Rev. 16:3. 2008).

Another approach to the treatment of schizophrenia has been use ofmuscarinic agonists. Muscarinic receptors are G-protein linked receptorsthat bind the neurotransmitter acetylcholine. (Eglen R M. Auton AutacoidPharmacol 26: 219. 2006). To date, five subtypes of muscarinic receptorhave been identified and are generally labeled M1, M2, M3, M4, and M5,respectively. (Caulfield M P et al. Pharmacol. Rev. 50: 279. 1998).These muscarinic subtypes vary in terms of the affinity of variousagonists and antagonists for the receptors. A number of lines ofevidence have suggested that the muscarinic system plays a significantrole in the pathology of schizophrenia. In particular, decreasedexpression of M1 and M4 receptor subtypes has been noted in post-mortemstudies in deceased schizophrenic patients. (Dean et al. Mol Psych. 1:54. 1996). Likewise, SPECT imaging studies have shown decreasedmuscarinic availability in schizophrenia. (Raedler et al. Am JPsych.160:118. 2003).

There is also pharmacological evidence implicating activation ofmuscarinic receptors as a potential therapeutic approach toschizophrenia. For example, the muscarinic antagonist scopolamine, whichis used to treat motion sickness, produces cognitive impairment anddelusions of the type seen in schizophrenia. (Ellis et al. Int. J.Neuropsychopharmacol. 9:175. 2006). More selective M1 agonists have beensuggested to potentiate glutamate signaling which could help exert atherapeutic effect. (Jones et al. J. Neurosci. 28:10422. 2008). In adouble-blind placebo controlled trial of schizophrenic patients usingxanomeline, which has preferential activity at the M1 and M4 receptors,alleviation of schizophrenia was observed. (Shekhar et al. Am. J. Psych.165: 1033. 2008). However, because xanomeline also bound to subtypes ofreceptors other than M1, a number of various serious side effects wereobserved including GI side effects, cardiac side effects and problemswith hyper-salivation.

To date, nobody has been able to harness the approach of employingmuscarinic agonists because of the side effects associated with theagents' binding certain muscarinic receptor subtypes. A need exists fora method of using muscarinic agonists and for a medicament employingsuch muscarinic agonists that would allow for the therapeutic effectsassociated with activation of muscarinic receptors, but with fewer sideeffects.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to a method of treatingdiseases or conditions ameliorated by activation of the muscarinicsystem by administering one or more muscarinic “Activators” (e.g.,agonist, partial agonist, co-agonist, physiological agonist,potentiator, stimulator, allosteric potentiator, positive allostericmodulator or allosteric agonist) and one or more muscarinic “Inhibitors”(e.g., antagonist, partial antagonist, competitive antagonist,non-competitive antagonist, uncompetitive antagonist, silent antagonist,inverse agonist, reversible antagonist, physiological antagonist,irreversible antagonist, inhibitor, reversible inhibitor, irreversibleinhibitor, negative allosteric modulator, or allosteric antagonist). Ina preferred embodiment, such diseases include schizophrenia and relateddisorders. In a preferred embodiment, a single muscarinic Activator anda single muscarinic Inhibitor are used. In a preferred embodiment, thecombination of the Activator and Inhibitor has a score (“Theta score”)above 230 as determined by in silico testing using a proprietaryalgorithm as described herein. In another embodiment, more than onemuscarinic Activator and/or more than one muscarinic Inhibitor are used.

In another embodiment of the invention, the method of treatment can beapplied to a mammal. In another embodiment, the mammal is a human being.

In one embodiment of the invention, the use of the Inhibitor alleviatesthe side effects associated with use of the Activator. In anotherembodiment, use of the Inhibitor allows for a higher maximum tolerateddose of the Activator.

In one embodiment, the muscarinic Activator may be taken sequentiallywith the Inhibitor. In another embodiment of the invention, themuscarinic Activator may be taken concurrently with the Inhibitor. In apreferred embodiment of the invention, the Activator and Inhibitor areformulated to be contained in the same dosage form or dosage vehicle. Inanother embodiment of the invention, the muscarinic Activator andInhibitor are formulated to be in separate dosage forms or dosagevehicles. In one embodiment, the Activator and Inhibitor are formulatedin an immediate release dosage form. In another embodiment, Activatorand Inhibitor are formulated in a controlled release dosage form. Inanother embodiment, either the Activator or the Inhibitor is formulatedin an immediate release dosage form, while the other is formulated in acontrolled release dosage form.

In another embodiment of the invention, the muscarinic Activator andInhibitor can be taken orally. The Activator and Inhibitor may be givenorally in tablets, troches, liquids, drops, capsules, caplets and gelcaps or other such formulations known to one skilled in the art. Otherroutes of administration can include but are not limited to: parenteral,topical, transdermal, ocular, rectal, sublingual, and vaginal.

In another embodiment of the invention, the muscarinic Activator andInhibitor are administered either simultaneously or consecutively withother therapies for schizophrenia. In one embodiment of the invention,the muscarinic Activator and Inhibitor are used simultaneously orsequentially with psychotherapy. In another embodiment of the invention,the muscarinic Activator and Inhibitor are administered eithersimultaneously or consecutively with other pharmacological therapies.Pharmacological therapies could include but are not limited to:antipsychotics, anxiolytics, anti-depressants, sedatives, tranquilizersand other pharmacological interventions known to one skilled in the art.

A separate embodiment of the invention is a medicament comprising both amuscarinic Activator and a muscarinic Inhibitor. In a preferredembodiment, the combination of the Activator and Inhibitor have a thetascore above 230 as determined by in silico testing using a proprietaryalgorithm as described herein.

In another embodiment of the invention, the medicament can be takenorally. The medicament may be given orally in tablets, troches, liquids,drops, capsules, caplets and gel caps or other such formulations knownto one skilled in the art. Other routes of administration can includebut are not limited to: parenteral, topical, transdermal, ocular,rectal, sublingual, and vaginal.

In another embodiment of the invention, the medicament can beadministered in conjunction with other therapies. In one embodiment ofthe invention, the medicament is used simultaneously or sequentiallywith psychotherapy. In another embodiment of the invention, themedicament is administered either simultaneously or consecutively withother pharmacological therapy. Such pharmacological therapy couldinclude but is not limited to: antipsychotics, anxiolytics,anti-depressants, sedatives, tranquilizers and other pharmacologicalinterventions known to one skilled in the art.

These and other embodiments of the invention, and their features andcharacteristics, will be described in further detail in the descriptionand claims that follow.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 illustrates the relationships among p-Scores, Subscores, andTheta Scores in accordance with the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

For convenience, before further description of the present invention,certain terms employed in the specification, examples and appendedclaims are collected here. These definitions should be read in light ofthe remainder of the disclosure and understood as by a person of skillin the art. Unless defined otherwise, all technical and scientific termsused herein have the same meaning as would be understood by a person ofordinary skill in the art.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e. to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The terms “comprise” and “comprising” are used in the inclusive, opensense, meaning that additional elements may be included.

The term “consisting” is used to limit the elements to those specifiedexcept for impurities ordinarily associated therewith.

The term “consisting essentially of” is used to limit the elements tothose specified and those that do not materially affect the basic andnovel characteristics of the material or steps.

As used herein, unless otherwise specified, the term “controlledrelease” is defined as a prolonged release pattern of one or more drugs,such that the drugs are released over a period of time. A controlledrelease formation is a formulation with release kinetics that result inmeasurable serum levels of the drug over a period of time longer thanwhat would be possible following intravenous injection or followingadministration of an immediate release oral dosage form. Controlledrelease, slow release, sustained release, extended release, prolongedrelease, and delayed release have the same definitions for the presentinvention.

The term “including” is used herein to mean “including but not limitedto.” “Including” and “including but not limited to” are usedinterchangeably.

The term “mammal” is known in the art, and exemplary mammals includehumans, primates, bovines, porcines, canines, felines, and rodents(e.g., mice and rats).

The terms “parenteral administration” and “administered parenterally”are art-recognized and refer to modes of administration other thanenteral and topical administration, usually by injection, and includes,without limitation, intravenous, intramuscular, intraarterial,intrathecal, intracapsular, intraorbital, intracardiac, intradermal,intraperitoneal, transtracheal, subcutaneous, subcuticular,intra-articular, subcapsular, subarachnoid, intraspinal, andintrasternal injection and infusion.

A “patient,” “subject” or “host” to be treated by the subject method maymean either a human or non-human mammal.

The term “pharmaceutically-acceptable carrier” is art-recognized andrefers to a pharmaceutically-acceptable material, composition orvehicle, such as a liquid or solid filler, diluent, excipient, solventor encapsulating material, involved in carrying or transporting anysubject composition or component thereof from one organ, or portion ofthe body, to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the subjectcomposition and its components and not injurious to the patient. Someexamples of materials that may serve as pharmaceutically acceptablecarriers include: sugars, such as lactose, glucose and sucrose;starches, such as corn starch and potato starch; cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients,such as cocoa butter and suppository waxes; oils, such as peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols, such as propylene glycol; polyols, such asglycerin, sorbitol, mannitol and polyethylene glycol; esters, such asethyl oleate and ethyl laurate; agar; buffering agents, such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol; phosphatebuffer solutions; and other non-toxic compatible substances employed inpharmaceutical formulations.

The term “pharmaceutically-acceptable salts,” used interchangeably with“salts,” is art-recognized and refers to salts prepared from relativelynon-toxic acids or bases including inorganic acids and bases and organicacids and bases, including, for example, those contained in compositionsof the present invention. Suitable non-toxic acids include inorganic andorganic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic,citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric acid, p-toluenesulfonic, hydrochloric,hydrobromic, phosphoric, and sulfuric acids and the like.

The term “treating” is art-recognized and refers to curing as well asameliorating at least one symptom of any condition or disorder.

The term “therapeutic agent” is art-recognized and refers to anychemical moiety that is a biologically, physiologically, orpharmacologically active substance that acts locally or systemically ina subject. Examples of therapeutic agents, also referred to as “drugs,”are described in well-known literature references such as the MerckIndex (14^(th) edition), the Physicians' Desk Reference (64^(th)edition), and The Pharmacological Basis of Therapeutics (12^(th)edition) , and they include, without limitation, medicaments; vitamins;mineral supplements; substances used for the treatment, prevention,diagnosis, cure or mitigation of a disease or illness; substances thataffect the structure or function of the body, or pro-drugs, which becomebiologically active or more active after they have been placed in aphysiological environment.

The term “psychotherapy” refers to use of non-pharmacological therapiesin which those skilled in the art use a variety of techniques thatinvolve verbal and other interactions with a patient to affect apositive therapeutic outcome. Such techniques include, but are notlimited to, behavior therapy, cognitive therapy, psychodynamic therapy,psychoanalytic therapy, group therapy, family counseling, art therapy,music therapy, vocational therapy, humanistic therapy, existentialtherapy, transpersonal therapy, client-centered therapy (also calledperson-centered therapy), Gestalt therapy, biofeedback therapy, rationalemotive behavioral therapy, reality therapy, response based therapy,Sandplay therapy, status dynamics therapy, hypnosis and validationtherapy. It is further understood that psychotherapy may involvecombining two or more techniques and that a therapist can select andadjust the techniques based on the needs of the individual patient andthe patient's response.

The term “Muscarinic Disorder” refers to any disease or condition thatis ameliorated by activation of the muscarinic system. Such diseasesinclude ones in which direct activation of muscarinic receptorsthemselves or inhibition of cholinesterase enzymes has produced atherapeutic effect.

The terms “Diseases Related To Schizophrenia” and “Disorders Related ToSchizophrenia” include, but are not limited to, schizo-affectivedisorder, psychosis, delusional disorders, psychosis associated withAlzheimer's disease, psychosis associated with Parkinson's disease,psychotic depression, bipolar disorder, bipolar with psychosis or anyother disease with psychotic features.

The term “Movement Disorders” includes, but is not limited to, Gilles dela Tourette's syndrome, Friederich's ataxia, Huntington's chorea,restless leg syndrome and other diseases or disorders whose symptomsinclude excessive movements, ticks and spasms.

The term “Mood Disorders” includes major depressive disorder, dysthymia,recurrent brief depression, minor depression disorder, bipolar disorder,mania and anxiety.

The term “Cognitive Disorders” refers to diseases or disorders that aremarked by cognitive deficit (e.g., having abnormal working memory,problem solving abilities, etc.). Diseases include but are not limitedto Alzheimer's disease, Parkinson's Disease, dementia (including, butnot limited to, AIDS related dementia, vascular dementia, age-relateddementia, dementia associated with Lewy bodies and idiopathic dementia),Pick's disease, confusion, cognitive deficit associated with fatigue,learning disorders, traumatic brain injury, autism, age-relatedcognitive decline, and Cushing's Disease, a cognitive impairmentassociated with auto-immune diseases.

The term “Attention Disorders” refers to diseases or conditions that aremarked by having an abnormal or decreased attention span. Diseasesinclude but are not limited to attention hyperactivity deficit disorder,attention deficit disorder, Dubowitz Syndrome, FG Syndrome, Down'sSyndrome, growth delay due to insulin-like growth factor I deficiency,hepatic encephalopathy syndrome, and Strauss Syndrome.

The term “Addictive Disorders” refers to diseases or conditions markedby addiction or substance dependence as defined by the Diagnostic &Statistical Manual IV. Such disorders are characterized by physicaldependence, withdrawal and tolerance to a particular substance. Suchsubstances include but are not limited to alcohol, cocaine,amphetamines, opioids, benzodiazepines, inhalants, nicotine,barbiturates, cocaine and cannabis. Addictive Disorders can alsoencompass behaviors that a patient does in a compulsive, continualmanner despite clear negative consequences. For instance, ludomania isrecognized by those skilled in the art as being an addictive behaviorthat often has devastating consequences.

The term “Activator” means a molecule that can be described as anagonist, partial agonist, co-agonist, physiological agonist,potentiator, stimulator, allosteric potentiator, positive allostericmodulator, allosteric agonist or a molecule that increases the activityor signaling of muscarinic receptors through direct or indirect means.

The term “Inhibitor” means a molecule that can be described as anantagonist, partial antagonist, competitive antagonist, non-competitiveantagonist, uncompetitive antagonist, silent antagonist, inverseagonist, reversible antagonist, physiological antagonist, irreversibleantagonist, inhibitor, reversible inhibitor, irreversible inhibitor,negative allosteric modulator, allosteric antagonist or a molecule thatdecreases the activity or signaling of muscarinic receptors throughdirect or indirect means.

The term “maximum tolerated dose” means the highest dose of a drug ortherapeutic that can be taken by patients without the patients'experiencing intolerable side effects. The maximum tolerated dose istypically determined empirically in clinical trials.

The term “Muscarinic receptors” refers to G-protein linked receptorsthat bind the neurotransmitter acetylcholine, and to date, five subtypesof muscarinic receptor have been identified. “M1” means the subtype onemuscarinic receptor. “M2” means the subtype two muscarinic receptor.“M3” means the subtype three muscarinic receptor. “M4” means the subtypefour muscarinic receptor. “M5” means the subtype five muscarinicreceptor.

The term “Antipsychotic” refers to a drug that diminishes psychosis,hallucinations or delusions. Antipsychotics can include, but are notlimited to: Haloperidol, droperidol, chlorpromazine, fluphenazine,perphenazine, prochlorperazine, thioridazine, trifluoperazine,mesoridazine, periciazine, promazine, triflupromazine, levomepromazine,promethazine, pimozide, chlorprothixene, flupenthixol, thiothixene,zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine,ziprasidone, amisulpride, asenapine, paliperidone, zotepine,aripiprazole, bifeprunox, and tetrabenazine.

The term “Anxiolytics” refers to drugs that reduce anxiety, fear, panicor related feelings. Such drugs include, but are not limited to:benzodiazepines (e.g., alprazolam, chlordiazepoxide, clonazepam,clorazepate, diazepam, lorazepam), buspirone, barbiturates (e.g.,amobarbital, pentobarbital, secobarbital, phenobarbitol) andhydroxyzine.

The term “Anti-depressants” refers to drugs that alleviate depressionand related conditions (e.g., dysthymia) and include, but are notlimited to: Selective serotonin-reuptake inhibitors (e.g., citalopram,escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline),serotonin-norepinephrine reuptake inhibitors (e.g., desvenlafaxine,duloxetine, milnacipram, venlafaxine), mianserin, mirtazapin,norepinephrine reuptake inhibitors (e.g., atomoxetine, mazindol,reboxetine, viloxazine), bupropion, tianeptine, agomelatine, trycyclicantidepressants (e.g., amitriptyline, clomipramine, doxepin, imipramine,trimipramine, desipramine, nortriptyline, protriptyline), monoamineoxidase inhibitors (e.g., isocarboxazid, moclobemide, phenelzine,selegiline, tranylcypromine).

The terms “Sedatives” or “tranquilizers” refer to drugs that inducesomnolence, promote a feeling of being tired or desire to sleep orpromote a state of unconsciousness. Such drugs include but are notlimited to benzodiazepines, barbiturates (e.g., amobarbital,pentobarbital, secobarbital, phenobarbitol), eszopiclone, zaleplon,zolpidem, zopiclone.

The term “Theta Score” is defined as the numerical value assigned by anin silico algorithm described herein used to predict the overallefficacy and side effects of any given combination of a MuscarinicActivator and a Muscarinic Inhibitor.

Introduction

The present invention relates to the method of use of one or moreActivators and Inhibitors of muscarinic receptors in combination fortreatment of various disorders that can be ameliorated by activation ofthe muscarinic system. The present invention also describes a medicamentcomprising one or more Activators and one or more Inhibitors ofmuscarinic receptors. Use of muscarinic Activators has previously beenhypothesized to be useful for various central nervous system relatedconditions. In particular, activation of the M1 and M4 receptor subtypescould prove to be of therapeutic value. However, no one has been able toadvance M1 and M4 muscarinic Activators through clinical development toreceive regulatory approval for CNS indications because of unacceptableside effects. For instance, while Activators of M1 and M4 muscarinicreceptors have been suggested to be efficacious treatments forschizophrenia (Shekhar et al. Am J Psychiatry. 165:1033. 2008; Shirey etel. Nature Chem Biol. 4:41. 2007), the binding by those Activators tosubtypes of muscarinic receptors besides M1 and M4 results in sideeffects which have prevented use of muscarinic Activators in the clinic.(Shekhar et al. Am. J. Psych. 165: 1033.2008). For instance, in bothphase I and subsequent trials, the muscarinic agonist xanomeline hadunacceptable GI side effects as well as other side effects primarilylinked to binding of muscarinic receptors besides M1 and M4. (Sramek etal. The Journal of Clinical Pharmacology. 35:800. 1995), (Cutler &Sramek. Eur. J. Clin. Pharmacol. 48:421-428. 1995), (Bodick et al. ArchNeuro 54:465-473. 1997). By combining a muscarinic Activator with anInhibitor, it is possible to achieve the desired therapeutic effectwhile diminishing or eliminating the side effects associated withunwanted subtype binding.

Muscarinic Inhibitors are used for treatment of overactive bladder andpulmonary disorders and have been suggested for treatment of otherdisorders. (Witte LP et al. Curr. Opin. Urol. 1:13. 2009). Groups haveoutlined use of muscarinic Inhibitors with drugs in other classes toachieve a greater effect for treatment of a disease. For example, WO2008/121268 suggests a combination for the treatment of lower urinarytract symptoms (LUTS) consisting of a beta-3 adrenergic agonist, whichon its own has been investigated for the treatment of LUTS, and amuscarinic antagonist. Others have suggested combining specificmuscarinic Activators or Inhibitors with other specific therapeuticagents other than muscarinic agents to further have a therapeutic effect(e.g., WO 2009/037503, WO 2009/036243, WO 2008/104776, WO 2008/096136,WO 2008/096126, WO 2008/096121, WO 2008/096111, WO 2007/127196, WO2007/125293, EP 2002843, EP 2002844, U.S. Pat. No. 5,744,476, U.S. Pat.No. 7,524,965, U.S. 2005/0267078, U.S. 2006/0189651, and U.S.2008/0045565). U.S. 2006/0287294 A1 outlines use of aspartyl proteaseinhibitors with either an M1 agonist or an M2 antagonist for treatmentof various diseases, including improvement of cognitive deficit. Both M1Activators and M2 Inhibitors themselves (Carey et al. Eur J Pharmacol431:198. 2001.) have been suggested to be useful treatments forcognitive deficit, and the rationale for the combination with theaspartyl protease inhibitor was to enhance the effects of the aspartylprotease inhibitor. No suggestion was made of combining the M1 Activatorwith the M2 Inhibitor, and both compounds would be capable of reachingand would be active in the central nervous system. U.S. Pat. No.5,480,651 discloses use of agents that increase acetylcholine in thesynapse or that activate the nicotinic acetylcholine receptors, followedby administration of an acetylcholine receptor antagonist to relievecraving associated with nicotine addiction. The preferred compositionuses physostigmine which is an inhibitor of acetylcholinesterase, asopposed to a muscarinic Activator which would not activate the nicotinicacetylcholine receptors. WO 03/092580 discloses compounds that can actsimultaneously as muscarinic Activators at certain receptor subtypes andantagonists at others. Groups have used various muscarinic Activatorswith muscarinic Inhibitors in the context of trying to differentiate therole of various muscarinic subtypes in drug pharmacology or normalphysiology without suggesting a therapeutic use of the combination. Suchstudies include use of cellular assays starting from animal materials.(e.g., Iwanaga K. et al. J. Pharmacol. Sci. 110:306. 2009). In U.S.2009/0318522, Paborji discloses use of a peripherally-acting muscarinicantagonist targeting the M2 and M3 receptors for the treatment ofoveractive bladder. The Paborji publication also discloses use of aperipherally-acting muscarinic M2/M3 agonist to counteract dry mouthassociated with the peripherally-acting M2/M3 muscarinic antagonist.Paborji's approach does not, however, relate to activity at muscarinicreceptors in the CNS, which is of critical importance for the workdescribed herein, nor does it pertain to activity at either the M1 or M4receptor. Paborji's approach is highly limited to a specific muscarinicinhibitor and does not provide any selection criteria to identifypreferred or specific combinations of muscarinic Activators with themuscarinic antagonist, in spite of the prohibitively large number ofpotential combinations for which experimental testing could be done.

Method Of Using Muscarinic Activators In Combination With MuscarinicInhibitors

In one embodiment of the invention, one or more muscarinic Activatorsare used in combination with one or more Muscarinic Inhibitors fortreatment of Muscarinic Disorders. In a preferred embodiment, suchdiseases or disorders include schizophrenia and Diseases Related toSchizophrenia. In another embodiment one or more muscarinic Activatorsare used in combination with one or more Muscarinic Inhibitors fortreatment of Mood Disorders. In another embodiment, one or moremuscarinic Activators are used with one or more muscarinic Inhibitors totreat Movement Disorders. In another embodiment, one or more muscarinicActivators are used with one or more muscarinic Inhibitors to treatCognitive Disorders, including using the combination to enhancecognitive function not associated with a specific pathology. Forinstance, improvement in cognition could be important in undertakingcomplex tasks. In another embodiment, one or more muscarinic Activatorsare used with one or more muscarinic Inhibitors to treat AttentionDisorders. Outside of disease treatment, enhancement of attention couldimprove learning and decrease symptoms associated with fatigue due toboth lack of sleep and circadian rhythm disturbances such as jet lag. Inanother embodiment, one or more muscarinic Activators are used with oneor more muscarinic Inhibitors to treat Addictive Disorders.

In another embodiment, the combination of one or more muscarinicActivators with one or more Muscarinic Inhibitors can be used to treatMuscarinic Disorders which are characterized by an amelioration ofsymptoms in response to inhibitors of cholinesterase enzymes. Whilecholinesterase inhibitors have proven therapeutic for certain diseases(e.g., Alzheimer's disease), the use of such inhibitors is limited dueto toxicity. In fact, powerful chemical weapons such as sarin gas exerttheir toxic effects by inhibiting acetylcholinesterase (sarin gasmaterial safety data sheet 103d Congress, 2d Session. United StatesSenate. May 25, 1994. http://www.gulfweb.org/bigdoc/report/appgb.html).The combination of one or more muscarinic Activators with one or moreMuscarinic Inhibitors represents not only a safer method of treatment ofthose diseases shown to be response to cholinesterase inhibitors, butalso a more effective one given the limitations on currentcholinesterase inhibitors.

In one embodiment, the combination of one or more muscarinic Activatorswith one or more Muscarinic Inhibitors is used to treat an animal. In afurther embodiment, the animal is a mammal. In a preferred embodiment,the mammal is a human being. In one embodiment, a single muscarinicActivator and a single muscarinic Inhibitor are used. In anotherembodiment more than one muscarinic Activator and/or more than onemuscarinic Inhibitor is used.

In one embodiment, use of the Inhibitor decreases the side effectsassociated with use of the Activator. Such side effects include, but arenot limited to, GI side effects, cardiac side effects, excessivesweating and excessive salivation. Use of one or more Inhibitors incombination with one or more Activators may allow the Activators to beused clinically when the Activators may not otherwise be used clinicallydue to the their side effects. In another embodiment, use of theInhibitor in conjunction with the Activator allows for the Activator toachieve a higher maximum tolerated dose than the Activator wouldotherwise achieve.

Various time and resource intensive methods may be used to demonstrateboth the efficacy of combination of the Activator and Inhibitor for theaforementioned embodiments. For example animal models have been used todemonstrate the efficacy of new therapeutics for schizophrenia,including both pharmacological models (e.g., ketamine model) and geneticmodels. (e.g., DISCI mouse) (Dawe G S et al. Ann Acad Med Singapore.38:425. 2009; Desbonnet L. Biochem Soc Trans. 37:308. 2009; Geyer M A.Neurotox Res. 14:71. 2008). Likewise, animal models including rodents,dogs and non-human primates can be used to demonstrate the side effectprofile of pharmacological agents. Animal models serve as anexperimental proxy for humans, but may suffer from deficienciesassociated with the physiological differences between human and animalsand thus may have limited predictive power for translation to humanexperiments, particularly for central nervous system disorders.Alternatively, the combination can be tried in controlled clinicaltrials of people. Standard measures based on patient self-report can beused by those skilled in the art to assess various side effects such asGI discomfort. As another example, objective physiological measures(e.g., EKGs) may be used by those skilled in the art. A set of standardmeasures has also been developed to assess schizophrenia symptomsincluding the Brief Psychiatric Rating Scale (BPRS), the Positive andNegative Syndrome Scale (PANSS) and Clinical Global Impression (CGI).(Mortimer A M. Br J Psychiatry Suppl. 50:s7. 2007). Typically, clinicaltrials are conducted in a double blinded manner in which one group ofpatients receives an inactive placebo and the other group the activeintervention.

In one embodiment of the invention, the muscarinic Activator isadministered concurrently with the muscarinic Inhibitor. In anotherembodiment, the muscarinic Inhibitor is administered consecutively withthe Activator. In further embodiment, the muscarinic Activator isadministered prior to administration of the muscarinic Inhibitor. Inanother embodiment, the muscarinic Inhibitor is administered prior toadministration of the muscarinic Activator. In one embodiment, themuscarinic Inhibitor is administered within one hour of administrationof the muscarinic Activator. In another embodiment, the muscarinicInhibitor is administered within 30 minutes of administration of themuscarinic Activator. In another embodiment, the muscarinic Inhibitor isadministered within 10 minutes of administration of the muscarinicActivator. In another embodiment, the muscarinic Inhibitor isadministered within one minute of administration of the muscarinicActivator. In another embodiment, the muscarinic Inhibitor isadministered within 30 seconds of administration of the muscarinicActivator. Prior to the start of a drug regimen of the type outlinedabove, there may be a lead-in period that lasts from one to fourteendays. During this lead-in period, the muscarinic Inhibitor may be givenby itself prior to the start of administration of the combination.

In one embodiment, from 10 micrograms to 10 grams of Activator is usedin the combination with the Inhibitor. In another embodiment, from 1milligram to 1 gram of Activator is used in the combination with theInhibitor. In a preferred embodiment, from 5 to 500 milligrams ofActivator is used. In one embodiment from 10 micrograms to 10 grams ofInhibitor is used in the combination with the Activator. In anotherembodiment, from 1 milligram to 1 gram of Inhibitor is used in thecombination with the Activator. In a preferred embodiment, from 2.5milligrams and 200 milligrams of Inhibitor is used.

In one embodiment, the muscarinic Activator and Muscarinic Inhibitor areadministered to a patient 6 times during a 24 hour period. In anotherembodiment, the muscarinic Activator and Muscarinic Inhibitor areadministered to a patient 5 times during a 24 hour period. In anotherembodiment, the muscarinic Activator and Muscarinic Inhibitor areadministered to a patient 4 times during a 24 hour period. In apreferred embodiment, the muscarinic Activator and Muscarinic Inhibitorare administered to a patient 3 times during a 24 hour period. Inanother preferred embodiment, the muscarinic Activator and MuscarinicInhibitor are administered to a patient 2 times during a 24 hour period.In another preferred embodiment, the muscarinic Activator and MuscarinicInhibitor are administered to a patient one time during a 24 hourperiod.

In Silico Testing Of Muscarinic Combinations

There are 65 unique muscarinic Activators and 114 unique muscarinicInhibitors that are currently known (Adis R&D Insight™, Pubmed, Web ofScience, U.S. FDA Orange Book, U.S. Pat. No. 5,852,029). Therefore,there exist 7,410 potential combinations in which a single muscarinicActivator could be paired with a single muscarinic Inhibitor. If onewere to combine more than one muscarinic Activator with one or moremuscarinic Inhibitors, then the number of combinations would be evengreater. While a number of animal models exist for relevant diseasessuch as schizophrenia (Dawe G S et al. Ann Acad Med Singapore. 38:425.2009; Desbonnet L. Biochem Soc Trans. 37:308. 2009; Geyer M A. NeurotoxRes. 14:71. 2008), animal models of complex diseases such asschizophrenia are imperfect, and thus the ability to predict humanefficacy and side effect burden based on animal data may be limited.Likewise, it is possible to test combinations in humans suffering from aparticular disease such as schizophrenia where there exist standardmeasuring scales (Mortimer A M. Br J Psychiatry Suppl. 50:s7. 2007) forboth efficacy of disease treatment as well as side effects. However,testing such a large number of combinations in either animal models ofdisease or more importantly in human clinical trials is practicallyimpossible as it would be prohibitively expensive, and could takedecades due to limitations in the number of existing skilledinvestigators and required time for patient recruitment.

Without a method of testing and predicting the efficacy of a givencombination, it is extremely difficult to predict a priori if such acombination will be efficacious. For instance, Medina et al. gave themuscarinic agonist xanomeline and the muscarinic antagonistmethscopolamine to investigate whether syncope, which is a side effectobserved with xanomeline, can be mediated by muscarinic antagonists(Medina et al. Hypertension. 29: 828. 1997). The group observed noeffect on syncope, which may reflect the lack of involvement of themuscarinic system in syncope or, alternatively, may reflect theincorrect selection of a muscarinic combination. Likewise, Maral et al.documented use of the muscarinic agonist RS-86 with the anticholinergicagent glycopyrrolate for treatment of Alzheimer's Disease (Maral et al.Neurology. 38:606. 1988). The approach did not result in any improvementin cognition despite use of escalating amounts of RS-86. U.S.2006/0194831 discloses use of a derivative of clozapine to activatemuscarinic receptors. While U.S. 2006/0194831 discloses that the use ofthe clozapine derivative can be combined with another therapy selectedfrom a broad list of therapies including use of a muscarinic antagonist,the publication provides no guidance or reasoning, for example, as towhy a particular agent should be selected from the broad list forcombination with the clozapine derivative, or why such a combinationwould be useful. U.S. Pat. No. 5,852,029, which discloses a particularmuscarinic agonist, mentions potential use of the particular agonistwith muscarinic antagonists to help eliminate side effects but does notprovide any criteria for selecting an appropriate antagonist.

Lack of success by groups such as Maral et al. points to the need tocarefully select and ideally test combinations of muscarinic Activatorsand Inhibitors. Given the impractical nature of physically testing sucha large number of combinations, we created an algorithm for in silicotesting to perform the extremely difficult task of predicting a priori,without in vivo testing, if a given combination will be efficacious andsafe. In order to carry out the in silico testing based on thealgorithm, we created an extensive database which captured the knowninformation about muscarinic Activators and Inhibitors. The process bywhich we created this unique algorithm, as well as the database ofmuscarinic agents and their properties, was both multi-phased andresource-intensive. First, we created a list of all known muscarinicActivators and Inhibitors. Next, we selected properties of muscarinicagents that are useful in predicting an efficacious and safe combinationand determined the relative importance of each property. We thenembarked on an exhaustive data-collection process to, wherever possible,gather data related to each property for each muscarinic Activator andInhibitor. With this data on-hand, we then created a computer-basedalgorithm, whereby a score is calculated for each property and eachcombination, such that these scores are then used to generate an overallscore for each combination. The scoring system was created such thathigher total scores (“Theta Scores”) are applied to combinations with ahigher probability to be efficacious with acceptable side effects.Therefore, by testing each combination with the algorithm, we created aprioritized list of combinations whereby combinations with higher scoresare more attractive candidates for clinical testing. Given theimpracticality of testing every possible combination in vivo,prioritization to select combinations for testing in humans is critical.

In order to evaluate different combinations of muscarinic Activator andInhibitors, we created a proprietary database of all known muscarinicActivators and Inhibitors (see Tables 1 and 2). This database wascreated through systematic reviews of a variety of resources in searchof all current and past programs related to muscarinic Activators andInhibitors. Our reviews included scholarly literature databases, such asPubmed and Web of Science, patent databases, such as Delphion, andpharmaceutical research and development databases, such as Adis R&DInsight™. We also reviewed drug package inserts, news databases, companywebsites, and conference abstracts. In all, we reviewed several thousandjournal publications, patents, Adis records, and other documents togenerate a comprehensive database of 65 muscarinic Activators and 114muscarinic Inhibitors.

We then selected properties useful in predicting whether a givencombination will be efficacious with acceptable side effects. Wedetermined, in other words, the criteria by which each combination maybe evaluated in order to generate a quantitative, predictive assessment.This process of selecting relevant properties was driven by rigorousinternal analyses and resulted in the identification of severalproperties that are typically not considered, and/or that are typicallythought to be unfavorable, but which we treated as favorable. Thecombination therapy approach in this application is significantlydifferent from typical combination therapy approaches, which entaillooking for synergistic efficacy of two agents. In the presentinvention, we look for one agent to eliminate the effects of the otheragent, which leads to unorthodox criteria for drug selection. Forexample, we evaluated each muscarinic Inhibitor based on efficacy datasuch that, in some cases, low or poor efficacy data was rewarded. Also,contrary to typical approaches, in some cases we rewarded muscarinicInhibitors for the side effects they exhibited during clinicaldevelopment. Since most muscarinic Inhibitors were tested for unrelatedindications, such as overactive bladder, efficacy for these unrelatedindications may be undesirable and may be predictive of a combinationwith potentially unacceptable side effects. For instance, excessiveurination is not a commonly reported side effect of muscarinicActivators. Therefore, having Inhibitors that have the greatest abilityto decrease micturition may present the greatest risk of causing urinaryretention without providing a benefit in the combination.

We rewarded certain side effects, particularly those known to beassociated with peripheral anticholinergic effects, because they maycounteract or lessen the impact of muscarinic Activator side effects.This combination of rewarding side effects and rewarding poor efficacyleads to the selection of a muscarinic Inhibitor that will havephysiological effects throughout the periphery, which is desired for theelimination of muscarinic Activator side effects. For example, if acompound demonstrated efficacy for the treatment of overactive bladderwithout any side effects, this would suggest that the compound wasinhibiting muscarinic receptors in the bladder, but not in thegastrointestinal tract or in the salivary glands to a significantdegree. Although such as compound would be ideal for a drug whoseintended purpose is the treatment of overactive bladder, such a compoundwould be unfavorable for the uses described herein. A more favorableInhibitor for the envisioned combination would demonstratepharmacological effects (i.e., side effects observed when treatingoveractive bladder) in the same organs where the Activator causesundesired side effects (e.g., the gastrointestinal tract). The rewardingof side effects and penalizing of efficacy stands in contrast to thetypical method for selecting pharmaceutical agents.

Our intensive selection process resulted in 95 relevant properties, onthe basis of which each of the 7,410 combinations of known muscarinicActivators and Inhibitors would be evaluated. The properties fell intothree general categories: properties related exclusively to muscarinicActivators; properties related exclusively to muscarinic Inhibitors; andproperties that combined attributes of both the Activator and Inhibitor.These classifications are discussed below in detail.

To collect data for each muscarinic Activator and Inhibitor based oneach property, we embarked on a rigorous data collection process usingmany of the same resources as those used in generating a database of allknown muscarinic Activators and Inhibitors. Again, our review spannedscholarly literature databases, such as Pubmed and Web of Science,patent databases, such as Delphion, pharmaceutical research anddevelopment databases, such as Adis R&D Insight™ and the U.S. FDA OrangeBook, as well as package inserts and other resources. This processdiffered, however, in the detailed and often quantitative nature of theinformation extracted. For example, we gathered and categorized allknown efficacy and side effect data for each muscarinic Activator andInhibitor. We also gathered all known data related to pharmacokineticsand pharmacodynamics. As new data becomes available for compoundscurrently in our database, or as information regarding potential newentries for our database becomes available, database updates may bemade, which would yield new theta scores. For example, MCD 386 is amuscarinic Activator for which additional data could result in increasedtheta scores for muscarinic Activator and Inhibitor combinations thatinclude MCD 386.

Using these data, we then created a computer-based algorithm to quantifythe relative probability that each muscarinic Activator and Inhibitorcombination will be efficacious with acceptable side effects. Thescoring system functions by applying a score to each combination basedon each property, which we call a p-score. Each p-score contributed toan overall calculation, such that a high p-score signified that acombination has an increased likelihood of being efficacious withacceptable side effects based on a given property. Since the algorithmtested a total of 7,410 possible combinations, each of which wasevaluated based on 95 p-scores, the algorithm summed a total of 703,950p-scores in calculating a unique overall score (a “Theta Score”) foreach combination (see FIG. 1).

Given the varied nature of data from one property to the next, a varietyof scoring methodologies were used to generate p-scores. In all cases,scoring methodologies were consistent within a given property andgenerated a maximum value of 10, which was then multiplied by a “weightfactor.” Weight factors were used to reflect the importance of eachproperty in predicting the probability that a combination is efficaciouswith acceptable side effects. Some properties, such as those relating tothe demonstration of efficacy for an agonist, have a stronger impact inassessing a preferred combination and were thus weighted more heavily.The baseline weight factor for all properties was 1, and the maximumweight factor used was 2.

The primary methodologies used in generating p-scores were ranking-basedscoring, binary scoring, and scoring by value cut-off. The mechanics ofeach of these methodologies are detailed below:

-   -   Ranking-based p-scores were generated using quantitative data,        such as efficacy measurements, and awarding the highest value        (e.g., a score of 10) to the most preferable data point, and the        lowest value (e.g., a score of 0) to the least preferable data        point. The remaining values were then distributed linearly, such        that less preferable data points were awarded proportionally        lower scores. Finally, a weight factor was applied to each value        by multiplying each score by a pre-determined weight that        reflected the importance of the given property. Take, for        example, the case where three muscarinic Inhibitors (Inhibitor        A, Inhibitor B, and Inhibitor C) are evaluated based on the        demonstrated reduction in urinary frequency (number of        micturitions per 24 hours), such that the minimum reduction, or        lowest efficacy, is desired. In this case, Inhibitor A shows a        reduction of 1 micturition per 24 hours, while Inhibitors B and        C show values of 2 and 4 respectively. To calculate each        p-score, since Inhibitor A demonstrated the most desirable        results, we first must give Inhibitor A a proportionally higher        value than B or C (e.g., Inhibitors A, B, and C are given values        of 1, ½, and ¼, respectively). We then linearly distribute these        values such that Inhibitor A receives a score of 10, Inhibitor B        a score of 5, and Inhibitor C a score of 2.5. Finally, these        scores are multiplied by a weight factor, which in this case        would be 1, giving final p-scores of 10, 5, and 2.5.    -   Binary p-scores were generated by assigning one of two values        relating to a binary property. Take, for example, the case of        two muscarinic Activators, A and B, which are evaluated based on        whether they have shown efficacy in human trials. Muscarinic        Activator A, which has shown efficacy, is awarded a value of 10,        while B, which has not, receives a score of 0. Since this        important property has a weight factor of 2, muscarinic        Activators A and B receive final p-scores of 20 and 0,        respectively.    -   Value cut-off p-scores were applied based on the group into        which a given value fell. This methodology was used for        non-binary cases where a ranking methodology is not preferred or        possible (e.g., scoring qualitative data, or scoring        quantitative data in which cut-offs are relevant). In these        cases, muscarinic Activators or Inhibitors whose values fall        into the most desirable category are awarded values of 10 (prior        to multiplication by the corresponding weight factor).

The p-scores applied to each combination were summed to generate threeunique Subscores: the Activator Independent Subscore, the InhibitorIndependent Subscore, and the Combination Subscore. The ActivatorIndependent Subscore represents an evaluation of each agonist based onproperties that are independent of the antagonist with which it iscombined (e.g., the demonstration of efficacy in human trials).Similarly, the Inhibitor Independent Subscore represents an evaluationof each antagonist based on properties that are independent of theagonist with which it is combined (e.g., level of CNS penetrance). TheCombination Subscore, in contrast, represents an evaluation based onproperties in which characteristics of both the agonist and antagonistare relevant (e.g., similarity of T_(max) based on pharmacokineticstudies). For both the Activator Independent Subscore and the InhibitorIndependent Subscore, the value was calculated by summing each p-scoreand then normalizing each score such that the highest ranking entry wasgiven a score of 100. Each lower ranking entry was thus increased ordecreased proportionally by the same factor as the highest rankingentry. In calculating the Combination Subscore, the same principle wasapplied; however, the maximum score given was 50.

Ultimately, the algorithm generated a final “Theta Score” for eachcombination such that, as the theta score increased, so did theprobability that the combination would produce efficacy with acceptableside effects. The Theta Score was calculated by summing the threeSubscores.

TABLE 1 List of Muscarinic Activators Muscarinic Activators 1 A 72055 2AF 125 3 AF 150(S) 4 AF 185 5 Alvameline 6 Amifostine 7 Arecolinetransdermal - Cogent Pharmaceuticals 8 Cevimeline 9 CI 1017 10 CMI 114511 CMI 936 12 CS 932 13 DM 71 14 FPL 14995 15 GSK 1034702 16 Himbacine17 Itameline 18 KST 2818 19 KST 5410 20 KST 5452 21 L 670548 22 L 68966023 L 696986 24 L 705106 25 LY 316108 26 MCD 386 27 Milameline 28Muscarinic receptor agonists - ACADIA/Allergan 29 NC 111585 30Nebracetam 31 NGX 267 32 Norclozapine 33 ORG 20091 34 PD 141606 35 PD142505 36 PD 151832 37 PDC 008004 38 Pilocarpine 39 Pilocarpine -Controlled Therapeutics 40 PTAC 41 Anavex Life Sciences preclinicalmuscarinic activator 42 Eli Lilly preclinical M1 receptor muscarinicactivator 43 Eli Lilly preclinical M4 receptor muscarinic activator 44TorryPines Therapeutics preclinical muscarinic activator 45 Banyupreclinical muscarinic activator 46 Mithridion preclinical muscarinicactivator 47 ACADIA/Sepracor preclinical muscarinic activator 48 ACADIApreclinical muscarinic activator 49 RU 35963 50 Sabcomeline 51 SDZ210086 52 SR 46559A 53 SR 96777A 54 Stacofylline 55 Talsaclidine 56Tazomeline 57 Thiopilocarpine 58 Ticalopride 59 U 80816 60 Vedaclidine61 WAY 131256 62 WAY 132983 63 Xanomeline 64 YM 796 65 YM 954

TABLE 2 List of Muscarinic Inhibitors Muscarinic Inhibitors 1 Aclidiniumbromide 2 Aclidinium bromide/formoterol 3 Acotiamide 4 AH 9700 5Alvameline 6 AQRA 721 7 AQRA 741 8 AZD 9164 9 BIBN 99 10 CEB 1957 11Clozapine extended release - Azur Pharma 12 Darenzepine 13 Darifenacin14 Darotropium bromide 15 Dextro-mequitamium iodide 16 Ebeinone 17Esoxybutynin 18 Espatropate 19 Fesoterodine 20Glycopyrrolate/indacaterol 21 Glycopyrronium bromide 22 GSK 1160724 23GSK 202405 24 GSK 573719 25 GSK 656398 26 GSK 961081 27 GYKI 46903 28Homatropine methylbromide 29 Imidafenacin 30 Inhaled glycopyrrolate -Novartis 31 Ipratropium bromide dry-powder inhalation - Dura/Spiros 32Ipratropium bromide dry-powder inhalation - ML Laboratories 33Ipratropium bromide hydrofluoroalkane inhalation - Boehringer Ingelheim34 Ipratropium bromide intranasal - Chiesi 35 Ipratropium bromidemetered solution inhalation - Sheffield 36 Ipratropiumbromide/xylometazoline 37 J 104129 38 J 106366 39 L 696986 40 LAS 3520141 Levosalbutamol/ipratropium inhalation solution - Arrow InternationalLimited/Sepracor 42 Liriodenine 43 LK 12 44 Mequitamium iodide 45Methantheline 46 Methantheline bromide 47 Methscopolamine bromide 48N-butylscopolamine 49 N-methylatropine 50 NPC 14695 51 NX 303 52Otenzepad 53 Oxybutynin - Labopharm 54 Oxybutynin - PenwestPharmaceuticals 55 Oxybutynin chloride - ALZA 56 Oxybutyninintravesical - Situs 57 Oxybutynin transdermal - Schwarz Pharma 58Oxybutynin transdermal - Watson 59 Oxybutynin transdermal gel - Antares60 Oxybutynin transmucosal - Auxilium 61 Oxybutynin vaginal - BarrLaboratories 62 PG 1000 63 Pirenzepine ophthalmic 64 Pirmenol 65 PNU200577 66 Promethazine/hydrocodone/paracetamol - Charleston Laboratories67 Propantheline 68 Propantheline bromide 69 Propiverine 70 PSD 506 71PTAC 72 QAT 370 73 Almirall muscarinic Inhibitor 74 Anavex Life Sciencesprimary muscarinic Inhibitor 75 Anavex Life Sciences secondarymuscarinic inhibitor 76 FF2 - Nuada 77 GlaxoSmithKline/Theravancemuscarinic Inhibitor 78 Chiesi Farmaceutici/SALVAT muscarinic inhibitor79 UCB muscarinic Inhibitor 80 Theravance primary muscarinic Inhibitor81 Theravance secondary muscarinic Inhibitor 82 Novartis muscarinicInhibitor 83 ACADIA/Sepracor muscarinic Inhibitor 84 Safetek muscarinicInhibitor 85 Revatropate 86 Rispenzepine 87 RL 315535 88 RO 465934 89SCH 211803 90 SCH 57790 91 Scopolamine intranasal - Nastech 92Scopolamine transmucosal - Anesta 93 Secoverine 94 S-ET 126 95Sintropium bromide 96 Solifenacin 97 Solifenacin/tamsulosin 98 SVT 4077699 TD 6301 100 Telenzepine 101 Temiverine 102 Tiotropium bromide 103Tolterodine 104 Tolterodine/tamsulosin 105 Tropenzilium 106 Trospiumchloride 107 Trospium chloride controlled release 108 Trospium chlorideinhalation 109 V 0162 110 YM 35636 111 YM 46303 112 YM 53705 113 YM58790 114 Zamifenacin

The algorithm was structured with inputs according to the following 3tables. The Property, Scoring Methodology, Criteria for a High Score,and Weight columns in each table represent the underlying inputs andmechanics used in calculating each Subscore.

TABLE 3 Mechanics of Activator Independent Subscore Activator SubscoreMechanics Weight Count Property Category Property Scoring MethodologyCriteria for a High Score Factor 1 Development Highest Phase Uniquevalue assigned to High stage of development 1 each dev. stage 2Development Highest Phase CNS Unique value assigned to High stage ofdevelopment 1 each dev. stage 3 Development Highest Phase US Uniquevalue assigned to High stage of development 1 each dev. stage 4 ROARoute of Administration Unique value assigned to Oral 1 each ROA 5Pharmacokinetics Tmax Ranked by Tmax value High Tmax 1 6Pharmacokinetics T(½) Ranked by T(½) value High T(½) 1 7 EfficacyDemonstrated Efficacy Binary scoring Efficacy shown 2 8 EfficacyDemonstrated Efficacy in Binary scoring Efficacy shown 2 Cognition 9Efficacy Demonstrated Efficacy in Binary scoring Efficacy shown 2Schizophrenia 10 Receptor Selectivity M2 Agonist? Binary scoring Not M2Agonist 1 11 Receptor Selectivity M3 Agonist? Binary scoring Not M3agonist 1 12 Receptor Selectivity M1/M2 ratio Ranked by ratio value Highratio 1 13 Receptor Selectivity M1/M3 ratio Ranked by ratio value Highratio 1 14 Receptor Selectivity M1/M5 ratio Ranked by ratio value Highratio 1 15 Receptor Selectivity M4/M2 ratio Ranked by ratio value Highratio 1 16 Receptor Selectivity M4/M3 ratio Ranked by ratio value Highratio 1 17 Receptor Selectivity M4/M5 ratio Ranked by ratio value Highratio 1 18 Receptor Selectivity M2/M3 ratio Ranked by ratio value Closeto 1 1 19 Receptor Selectivity M5/M2 ratio Ranked by ratio value Closeto 1 1 20 Receptor Selectivity M5/M3 ratio Ranked by ratio value Closeto 1 1

TABLE 4 Mechanics of Inhibitor Independent Subscore Inhibitor SubscoreMechanics Weight Count Property Category Property Scoring MethodologyCriteria for High Score Factor 1 Development Highest Phase Unique valueassigned to High stage of development 1 each dev. stage 2 DevelopmentHighest Phase US Unique value assigned to High stage of development 1each dev. stage 3 ROA Route of Administration Unique value assigned toOral 1 each ROA 4 Pharmacokinetics Tmax Ranked by Tmax value High Tmax 15 Pharmacokinetics T(½) Ranked by T(½) value High T(½) 1 6 CNSPenetrance CNS Penetrance Unique value assigned based Low penetrance 2on H, M, L penetrance 7 Receptor Selectivity M2/M1 ratio Ranked by ratiovalue High ratio 1 8 Receptor Selectivity M2/M4 ratio Ranked by ratiovalue High ratio 1 9 Receptor Selectivity M3/M1 ratio Ranked by ratiovalue High ratio 1 10 Receptor Selectivity M3/M4 ratio Ranked by ratiovalue High ratio 1 11 Efficacy Urinary Frequency Ranked by efficacyvalue Low efficacy 1 (# Micturitions per 24 hrs) -- Reduction 12Efficacy Urinary Frequency Ranked by efficacy value Low efficacy 1 (#Micturitions/24 hrs) -- % Reduction 13 Efficacy Urinary Frequency Rankedby efficacy value Low efficacy 1 (# Micturitions/24 hrs) -- % Reductionover Placebo 14 Efficacy Urinary Frequency Ranked by efficacy value Lowefficacy 1 (# Micturitions/24 hrs) -- Reduction over Placebo 15 EfficacyVolume Voided/micturition Ranked by efficacy value Low efficacy 1 (mL)-- Reduction 16 Efficacy Volume Voided/micturition Ranked by efficacyvalue Low efficacy 1 (mL) -- % Reduction 17 Efficacy VolumeVoided/micturition Ranked by efficacy value Low efficacy 1 (mL) -- %Reduction over Placebo 18 Efficacy Volume Voided/micturition Ranked byefficacy value Low efficacy 1 (mL) -- Reduction over Placebo 19 Efficacy# of Incontinence Eps/24 Ranked by efficacy value Low efficacy 1 hours-- % Reduction 20 Efficacy # of Incontinence Eps/24 Ranked by efficacyvalue Low efficacy 1 hours -- Reduction 21 Efficacy # of IncontinenceEps/week -- Ranked by efficacy value Low efficacy 1 % Reduction 22Efficacy # of Incontinence Eps/week -- Ranked by efficacy value Lowefficacy 1 Reduction 23 Efficacy # Urge incontinence eps/24 Ranked byefficacy value Low efficacy 1 hrs -- % Reduction 24 Efficacy # Urgeincontinence eps/24 Ranked by efficacy value Low efficacy 1 hrs --Reduction 25 Efficacy # Urge incontinence eps/ Ranked by efficacy valueLow efficacy 1 week -- % Reduction 26 Efficacy # Urge incontinence eps/Ranked by efficacy value Low efficacy 1 week -- Reduction 27 AdverseEvents Dry Mouth -- % increase Ranked by AE value Low AE values 1 overplacebo 28 Adverse Events Constipation -- % increase Ranked by AE valueLow AE values 1 over placebo 29 Adverse Events Dyspepsia -- % increaseRanked by AE value Low AE values 1 over placebo 30 Adverse EventsAbdominal Pain -- % increase Ranked by AE value Low AE values 1 overplacebo 31 Adverse Events Dry Mouth -- absolute % Ranked by AE value LowAE values 1 values 32 Adverse Events Constipation -- absolute % Rankedby AE value Low AE values 1 values 33 Adverse Events Dyspepsia --absolute % Ranked by AE value Low AE values 1 values 34 Adverse EventsAbdominal Pain -- absolute % Ranked by AE value Low AE values 1 values35 Adverse Events Constipation aggravated Ranked by AE value Low AEvalues 1 36 Adverse Events Nausea Ranked by AE value Low AE values 1 37Adverse Events Abdominal Distension Ranked by AE value Low AE values 138 Adverse Events Flatulence Ranked by AE value Low AE values 1 39Adverse Events Diarrhea Ranked by AE value Low AE values 1 40 AdverseEvents Vomiting Ranked by AE value Low AE values 1 41 Adverse Events UTIRanked by AE value Low AE values 1 42 Adverse Events Upper Respiratorytract Ranked by AE value Low AE values 1 infection 43 Adverse EventsInfluenza Ranked by AE value Low AE values 1 44 Adverse EventsPharyngitis Ranked by AE value Low AE values 1 45 Adverse EventsHeadache Ranked by AE value Low AE values 1 46 Adverse Events DizzinessRanked by AE value Low AE values 1 47 Adverse Events Vision BlurredRanked by AE value Low AE values 1 48 Adverse Events Dry Eyes Ranked byAE value Low AE values 1 49 Adverse Events Urinary Retention Ranked byAE value Low AE values 1 50 Adverse Events Dysuria Ranked by AE valueLow AE values 1 51 Adverse Events Edema Lower Limb Ranked by AE valueLow AE values 1 52 Adverse Events Edema peripheral Ranked by AE valueLow AE values 1 53 Adverse Events Fatigue Ranked by AE value Low AEvalues 1 54 Adverse Events Depression Ranked by AE value Low AE values 155 Adverse Events Insomnia Ranked by AE value Low AE values 1 56 AdverseEvents Cough Ranked by AE value Low AE values 1 57 Adverse Events DryThroat Ranked by AE value Low AE values 1 58 Adverse Events HypertensionRanked by AE value Low AE values 1 59 Adverse Events Asthenia Ranked byAE value Low AE values 1 60 Adverse Events Nasal dryness Ranked by AEvalue Low AE values 1 61 Adverse Events Back pain Ranked by AE value LowAE values 1 62 Adverse Events ALT increased Ranked by AE value Low AEvalues 1 63 Adverse Events GGT increased Ranked by AE value Low AEvalues 1 64 Adverse Events Rash Ranked by AE value Low AE values 1 Note:ALT = Alanine transaminase; GGT = Gamma-glutamyltransferase

TABLE 5 Mechanics of Combination Subscore Combination Subscore MechanicsWeight Count Property Category Property Scoring Methodology Criteria forHigh Score Factor 1 Pharmacokinetics Tmax Unique value given based onClose Tmax values 1 closeness of Tmax 2 Pharmacokinetics T(½) Uniquevalue given based on Close T(½) values 1 closeness of T(½) 3 MetabolismDrug-drug interaction Unique value assigned based on Low overall risk ofdrug-drug 1 potential H, M, or L degree of interaction, interactionspecifically regarding CYP 450 4 Receptor Selectivity (M1 Activatorselectivity/M1 Ranked by ratio value High ratio value (devalue if 1Inhibitor selectivity) ratio Inhibitor acts on M1, Activator is weak M1Activator) 5 Receptor Selectivity (M4 Activator selectivity/M4 Ranked byratio value High ratio value (devalue if 1 Inhibitor selectivity) ratioInhibitor acts on M4, Activator is weak M4 Activator) 6 ReceptorSelectivity (M3 Activator selectivity/M3 Ranked by ratio value Low ratiovalue (With M3 1 Inhibitor selectivity) ratio Activator, M3 Inhibitor isdesired) 7 Receptor Selectivity (M2 Activator selectivity/M2 Ranked byratio value Low ratio value (If M2 1 Inhibitor selectivity) ratioActivator, M2 Inhibitor is desired) 8 Receptor Selectivity (M5 Activatorselectivity/M5 Ranked by ratio value High ratio value 1 Inhibitorselectivity) ratio 9 Receptor Selectivity M2/M3 ratio comparison Rankedby ratio value Ratio value close to 1 1 10 Efficacy Reward specificcases of Case specific Case specific 1 Inhibitor AEs if “offsetting” anActivator AE 11 Adverse Events Reward specific cases of Case specificCase specific 1 Inhibitor AEs if “offsetting” an Activator AE Note: Incases where Activators inhibits a receptor, or where an Inhibitoractivates a receptor, receptor selectivity ratios are changed to equalone divided by the ratio for determining the p-score.

TABLE 6 Top 15 Combinations by Theta Score Activator InhibitorCombination Independent Independent Combination ID Combination ThetaScore Subscore Subscore Subscore 6355 Xanomeline & Trospium chloride 250100 100 50 5003 Sabcomeline & Trospium chloride 245 95 100 50 2611Milameline & Trospium chloride 243 98 100 45 6346 Xanomeline &Tolterodine 241 100 91 50 2602 Milameline & Tolterodine 239 98 91 505005 Sabcomeline & Trospium chloride 238 95 93 50 controlled release6357 Xanomeline & Trospium chloride 238 100 93 45 controlled release2613 Milameline & Trospium chloride 236 98 93 45 controlled release 6347Xanomeline & Darifenacin 235 100 95 40 6348 Xanomeline & Solifenacin 234100 94 40 4996 Sabcomeline & Solifenacin 229 95 94 40 5523 Talsaclidine& Trospium chloride 224 94 100 30 635 Cevimeline & Trospium chloride 21989 100 30 5515 Talsaclidine & Darifenacin 219 94 95 30 5516 Talsaclidine& Solifenacin 218 94 94 30 5525 Ttalsaclidine & Trospium chloride 217 9493 30 controlled release 5514 Talsaclidine & Tolterodine 215 94 91 306349 Xanomeline & Fesoterodine 215 100 85 30 627 Cevimeline &Darifenacin 214 89 95 30 637 Cevimeline & Trospium chloride 212 89 93 30controlled release

In a preferred embodiment of the invention, a combination of amuscarinic Activator and a muscarinic Inhibitor with a theta score of230 or greater as determined by in silico testing using the abovedescribed algorithm is used. In another embodiment of the invention, acombination of a muscarinic Activator and a muscarinic Inhibitor with atheta score of 200 or greater as determined by in silico testing usingthe above described algorithm is used. In another embodiment of theinvention, a combination of a muscarinic Activator and a muscarinicInhibitor with a theta score of 150 or greater as determined by insilico testing using the above described algorithm is used. In a furtherembodiment of the invention, a combination of a muscarinic Activator anda muscarinic Inhibitor with a theta score of 149 or lower as determinedby in silico testing using the above described algorithm is used.

In one embodiment, xanomeline is used as the muscarinic Activator incombination with the muscarinic Inhibitor. In another embodiment,xanomeline is administered to a patient from one time to five timesduring a 24 hour period. In a preferred embodiment, xanomeline isadministered from one time to three times during a 24 hour period. Inanother embodiment, from 25 milligrams to 700 milligrams of xanomelineis used during a 24 hour period. In a preferred embodiment, from 75milligrams to 300 milligrams of xanomeline is used during a 24 hourperiod.

In one embodiment, sabcomeline is used as the muscarinic Activator incombination with the muscarinic Inhibitor. In another embodiment,sabcomeline is administered to a patient from one time to five timesduring a 24 hour period. In a preferred embodiment, sabcomeline isadministered from one to three times during a 24 hour period. In anotherembodiment, from 50 micrograms to five milligrams of sabcomeline is usedduring a 24 hour period. In a preferred embodiment, from 150 microgramsto 450 micrograms of sabcomeline is used during a 24 hour period.

In one embodiment, milameline is used as the muscarinic Activator incombination with the muscarinic Inhibitor. In another embodiment,milameline is administered to a patient from one time to five timesduring a 24 hour period. In a preferred embodiment, milameline isadministered from one to three times during a 24 hour period. In anotherembodiment, from 0.5 milligrams to 50 milligrams of milameline is usedduring a 24 hour period. In a preferred embodiment, from four milligramsto 16 milligrams of milameline is used during a 24 hour period.

In one embodiment, talsaclidine is used as the muscarinic Activator incombination with the muscarinic Inhibitor. In another embodiment,talsaclidine is administered to a patient from one time to five timesduring a 24 hour period. In a preferred embodiment, talsaclidine isadministered from one to three times during a 24 hour period. In anotherembodiment, from five milligrams to 1 gram of talsaclidine is usedduring a 24 hour period. In a preferred embodiment, from 120 milligramsto 480 milligrams of talsaclidine is used during a 24 hour period.

In one embodiment, cevimeline is used as the muscarinic Activator incombination with the muscarinic Inhibitor. In another embodiment,cevimeline is administered to a patient from one time to five timesduring a 24 hour period. In a preferred embodiment, cevimeline isadministered from one to three times during a 24 hour period. In anotherembodiment, from 45 milligrams to 750 milligrams of cevimeline is usedduring a 24 hour period. In a preferred embodiment, from 90 milligramsto 360 milligrams of cevimeline is used during a 24 hour period.

In one embodiment, pilocarpine is used as the muscarinic Activator incombination with the muscarinic Inhibitor. In another embodiment,pilocarpine is administered to a patient from one time to five timesduring a 24 hour period. In a preferred embodiment, pilocarpine isadministered from one to three times during a 24 hour period. In anotherembodiment, from 7.5 milligrams to 500 milligrams of pilocarpine is usedduring a 24 hour period. In a preferred embodiment, from 30 milligramsto 200 milligrams of pilocarpine is used during a 24 hour period.

In one embodiment, trospium chloride is used as the muscarinic Inhibitorin combination with the muscarinic Activator. In another embodiment,trospium chloride is administered to a patient from one time to fivetimes during a 24 hour period. In a preferred embodiment, trospiumchloride is administered from one time to three times during a 24 hourperiod. In another embodiment, from five milligrams to 400 milligrams oftrospium chloride is used during a 24 hour period. In a preferredembodiment, from 20 milligrams to 200 milligrams of trospium chloride isused during a 24 hour period.

In one embodiment, trospium chloride extended release is used as themuscarinic Inhibitor in combination with the muscarinic Activator. Inanother embodiment, trospium chloride extended release is administeredto a patient from one time to five times during a 24 hour period. In apreferred embodiment, trospium chloride extended release is administeredfrom one to three times during a 24 hour period. In another embodiment,from five milligrams to 400 milligrams of trospium chloride extendedrelease is used during a 24 hour period. In a preferred embodiment, from20 milligrams to 200 milligrams of trospium chloride extended release isused during a 24 hour period.

In one embodiment, solifenacin is used as the muscarinic Inhibitor incombination with the muscarinic Activator. In another embodiment,solifenacin is administered to a patient from one time to five timesduring a 24 hour period. In a preferred embodiment, solifenacin isadministered from one time to three times during a 24 hour period. Inanother embodiment, from 0.25 milligrams to 100 milligrams ofsolifenacin is used during a 24 hour period. In a preferred embodiment,from 1 milligram to 30 milligrams of solifenacin is used during a 24hour period.

In one embodiment, tolterodine is used as the muscarinic Inhibitor incombination with the muscarinic Activator. In another embodiment,tolterodine is administered to a patient from one time to five timesduring a 24 hour period. In a preferred embodiment, tolterodine isadministered from one to three times during a 24 hour period. In anotherembodiment, from one milligram to 16 milligrams of tolterodine is usedduring a 24 hour period. In a preferred embodiment, from two milligramsto eight milligrams of tolterodine is used during a 24 hour period.

In one embodiment, fesoterodine is used as the muscarinic Inhibitor incombination with the muscarinic Activator. In another embodiment,fesoterodine is administered to a patient from one time to five timesduring a 24 hour period. In a preferred embodiment, fesoterodine isadministered from one to three times during a 24 hour period. In anotherembodiment, from two milligrams to 56 milligrams of fesoterodine is usedduring a 24 hour period. In a preferred embodiment, from four milligramsto 28 milligrams of fesoterodine is used during a 24 hour period.

In one embodiment, darifenacin is used as the muscarinic Inhibitor incombination with the muscarinic Activator. In another embodiment,darifenacin is administered to a patient from one time to five timesduring a 24 hour period. In a preferred embodiment, darifenacin isadministered from one to three times during a 24 hour period. In anotherembodiment, from 3.75 milligrams to 150 milligrams of darifenacin isused during a 24 hour period. In a preferred embodiment, from 7.5milligrams to 30 milligrams of darifenacin is used during a 24 hourperiod.

While the subject is being treated, the health of the patient may bemonitored by measuring one or more of the relevant indices atpredetermined times during the treatment period. Treatment, includingcomposition, amounts, times of administration and formulation, may beoptimized according to the results of such monitoring. The patient maybe periodically reevaluated to determine the extent of improvement bymeasuring the same parameters. Adjustments to the amount(s) of subjectcomposition administered and possibly to the time of administration maybe made based on these reevaluations.

Treatment may be initiated with smaller dosages that are less than theoptimum dose of the compound. Thereafter, the dosage may be increased bysmall increments until the optimum balance between therapeutic effectand side effects is attained.

Dosage Forms Of The Combination

In one embodiment, the muscarinic Activator and muscarinic Inhibitor arein different dosage forms or dosage vehicles. In a preferred embodiment,the muscarinic Activator and muscarinic Inhibitor are in the same dosageform or dosage vehicles. The dosage forms may include one or morepharmaceutically-acceptable carriers. The dosage forms may also includeone or more pharmaceutically-acceptable salts. The dosage forms may beadministered orally. The Activator and Inhibitor may be delivered orallyusing tablets, troches, liquids, emulsions, suspensions, drops,capsules, caplets or gel caps and other methods of oral administrationknown to one skilled in the art. The muscarinic Activator and Inhibitormay also be administered parentally. Other routes of administrationinclude but are not limited to: topical, transdermal, nasal, ocular,rectal, sublingual, inhalation, and vaginal. For topical and transdermaladministration, the Activator and Inhibitor may be delivered in a cream,gel, ointment, spray, suspension, emulsion, foam, or patch or by othermethods known to one skilled in the art. For nasal administration, theActivator and Inhibitor may be delivered by sprays, drops, emulsions,foams, creams, ointments or other methods known to one skilled in theart. For nasal administration, formulations for inhalation may beprepared as an aerosol, either a solution aerosol in which the activeagent is solubilized in a carrier, such as a propellant, or a dispersionaerosol, in which the active agent is suspended or dispersed throughouta carrier and an optional solvent. For ocular administration, theActivator and Inhibitor may be delivered in drops, sprays, injections,solutions, emulsions, suspensions, or ointments, or by other methodsknown to one skilled in the art. For rectal administration, theActivator and Inhibitor may be delivered using suppositories, enemas,creams, foams, gels, or ointments or by other methods known to oneskilled in the art. For sublingual administration, the Activator andInhibitor may be delivered in tablets, troches, liquids, emulsions,suspensions, drops, capsules, caplets or gel caps and by other methodsof oral administration known to one skilled in the art. Foradministration by inhalation, the Activator and Inhibitor may bedelivered in vapor, mist, powder, aerosol, or nebulized form, or byother methods known to one skilled in the art. For vaginaladministration, the Activator and Inhibitor may be delivered insolutions, emulsions, suspensions, ointments, gels, foams, or vaginalrings or by other methods known to one skilled in the art.

The muscarinic Activator and Inhibitor may be in a dosage form thatimmediately releases the drug. In an alternative embodiment, themuscarinic Activator and Inhibitor are in a controlled release dosageform. In one embodiment of the controlled release dosage form, theActivator and Inhibitor have similar release kinetics. In anotherembodiment, the Inhibitor is released prior to the Activator's beingreleased. In another embodiment, a three part release profile is usedsuch that the Inhibitor is released immediately, followed by theActivator in a controlled release fashion and then by the Inhibitor in acontrolled release fashion. In one embodiment, the muscarinic Activatorand Inhibitor are packaged in liposomes. In a further embodiment, theliposome comprises a phospholipid. In a further embodiment, thephospholipid in the liposome is selected from phosphatidylcholine (PC),phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine(PS), phosphatidylethanolamine (PE), phosphatidic acid (PA), eggphosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), eggphosphatidylinositol (EPI), egg phosphatidylserine (EPS), eggphosphatidylethanolamine (EPE), egg phosphatidic acid (EPA), soyphosphatidylcholine (SPC), soy phosphatidylglycerol (SPG), soyphosphatidylserine (SPS), soy phosphatidylinositol (SPI), soyphosphatidylethanolamine (SPE), soy phosphatidic acid (SPA),hydrogenated egg phosphatidylcholine (HEPC), hydrogenated soyphosphatidylcholine (HSPC), dipalmitoylphosphatidylcholine (DPPC),dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine(DMPC), dimyristoylphosphatidylglycerol (DMPG),dipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylcholine(DSPQ), distearoylphosphatidylglycerol (DSPG),dioleoylphosphatidyl-ethanolamine (DOPE),palmitoylstearoylphosphatidyl-choline (PSPC),palmitoylstearolphosphatidylglycerol (PSPG),mono-oleoyl-phosphatidylethanolarnine (MOPE), dilauroylethylphosphocholine (DLEP), dimyristoyl ethylphosphocholine (DMEP),dipalmitoyl ethylphosphocholine (DPEP), distearoyl ethylphosphocholine(DSEP), dimyristoylphosphatidic acid (DMPA), dipalmitoylphosphatidicacid (DPPA), distearoylphosphatidic acid (DSPA),dimyristoylphosphatidylinositol (DMPI), dipalmitoylphosphatidylinositol(DPPI), distearoylphosphatidylinositol (DSPI),dimyristoylphosphatidylserine (DMPS), dipalmitoylphosphatidylserine(DPPS), distearoylphosphatidylserine (DSPS), N-acylatedphosphorylethanolamine (NAPE), and combinations thereof.

In a further embodiment, the controlled release formulation comprises asemi-permeable membrane. The muscarinic Activator and muscarinicInhibitor may be in different membranes in the same formulation. Inanother embodiment, the muscarinic Activator and muscarinic Inhibitorcan be in different membranes in different formulations or dosingvehicles. In a further embodiment, the semi-permeable membrane comprisesa polymer. In a further embodiment, the controlled release formulationcomprises a matrix that suspends the muscarinic Activator(s) andmuscarinic Inhibitor(s). The muscarinic Activator and Inhibitor may bein separate matrices within the same medicament. In a furtherembodiment, the matrix comprises a polymer. In a further embodiment, thepolymer comprises a water soluble polymer. In a further embodiment, thewater soluble polymer is selected from Eudragit RL, polyvinyl alcohol,polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, polyethylene glycol, and mixturesthereof. In a further embodiment, the polymer comprises a waterinsoluble polymer. In a further embodiment, the water insoluble polymeris selected from Eudragit RS, ethylcellulose, cellulose acetate,cellulose propionate, cellulose acetate propionate, cellulose acetatebutyrate, cellulose acetate phthalate, cellulose triacetate, poly(methylmethacrylate), poly(ethyl methacrylate), poly(butyl methacrylate),poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecylmethacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate),poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutylacrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) lowdensity, poly(ethylene) high density, poly(propylene), poly(ethyleneterephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate),poly(vinyl chloride), polyurethane, and mixtures thereof. In a furtherembodiment, the matrix comprises a fatty compound. In a furtherembodiment, the fatty compound is a wax or glyceryl tristearate. In afurther embodiment, the polymer comprises a water soluble polymer and awater insoluble polymer. In a further embodiment, the matrix furthercomprises a fatty compound.

The muscarinic Activator and muscarinic Inhibitor may be in dosage formsthat use other methods of controlled release formulation known to oneskilled in the art (for example, Dixit & Puthli. J. Control Release.2:94. 2009; Mizrahi & Domb. Recent Pat Drug Deliv Formul. 2:108. 2008;Forqueri & Singh. Recent Pat Drug Deliv Formul. 3:40. 2009; Kalantzi etal. Recent Pat Drug Deliv Formul. 3:49. 2009; Iconomopoulou et al.Recent Pat Drug Deliv Formul. 2:94. 2008; Panos et al. Curr Drug DiscovTechnol. 5: 333. 2008; 2008. Wan et al. Nanomed. 2:483. 2007. Wang etal. Drug Delivery: Principles & Applications. Wiley 2005).

In another embodiment, the combination of the muscarinic Activator andInhibitor is used in combination with one or more therapies that caninclude both psychotherapy and drugs. Therapeutic agents include but arenot limited to antipsychotics, anxiolytics, anti-depressants, sedatives,tranquilizers and other pharmacological interventions known to oneskilled in the art. A therapeutic agent may fall under the category ofmore than one type of drug. For instance benzodiazepines can beconsidered anxiolytics, sedatives and tranquilizers.

Medicament Containing One Or More Muscarinic Activators & MuscarinicInhibitors

One embodiment of the invention is a medicament comprising one or moremuscarinic Activators and one or more muscarinic Inhibitors.

In one embodiment, from 10 micrograms to 10 grams of Activator is usedin the combination with the Inhibitor in the medicament. In anotherembodiment, from 1 milligram to 1 gram of Activator is used in thecombination with the Inhibitor. In another embodiment from 10 microgramsto 10 grams of Inhibitor is used in the combination with the Activator.In another embodiment, from 1 milligram to 1 gram of Inhibitor is usedin the combination with the Activator.

In one embodiment, the medicament is administered to a patient 6 timesduring a 24 hour period. In another embodiment, the medicament isadministered to a patient 5 times during a 24 hour period. In anotherembodiment, the medicament is administered to a patient 4 times during a24 hour period. In another embodiment, the medicament is administered toa patient 3 times during a 24 hour period. In another embodiment, themedicament is administered to a patient 2 times during a 24 hour period.In another embodiment, the medicament is administered to a patient onetime during a 24 hour period. In a preferred embodiment, the medicamentis administered from one to 3 times during a 24 hour period.

In one embodiment of the invention, the medicament contains acombination of a muscarinic Activator and a muscarinic Inhibitor with atheta score of 230 or greater as determined by in silico testing usingthe above described algorithm. In another embodiment of the invention,the medicament contains a combination of a muscarinic Activator and amuscarinic Inhibitor with a theta score of 200 or greater as determinedby in silico testing using the above described algorithm. In anotherembodiment of the invention, the medicament contains a combination of amuscarinic Activator and a muscarinic Inhibitor with a theta score of150 or greater as determined by in silico testing using the abovedescribed algorithm. In a further embodiment of the invention, themedicament contains a combination of a muscarinic Activator and amuscarinic Inhibitor with a theta score of 149 or lower as determined byin silico testing using the above described algorithm. In a furtherembodiment, xanomeline is used as the muscarinic Activator in themedicament. In another embodiment, the medicament contains from fivemilligrams to 700 milligrams of xanomeline. In a preferred embodiment,the medicament contains from 25 milligrams to 300 milligrams ofxanomeline.

In one embodiment, sabcomeline is used as the muscarinic Activator inthe medicament. In another embodiment, the medicament contains from 10micrograms to five milligrams of sabcomeline. In a preferred embodiment,the medicament contains from 50 micrograms to 450 micrograms ofsabcomeline.

In one embodiment, milameline is used as the muscarinic Activator in themedicament. In another embodiment, the medicament contains from 0.1milligrams to 50 milligrams of milameline. In a preferred embodiment,the medicament contains from one milligram to 16 milligrams ofmilameline.

In one embodiment, talsaclidine is used as the muscarinic Activator inthe medicament. In another embodiment, the medicament contains from onemilligram to one gram of talsaclidine. In a preferred embodiment, themedicament contains from 40 milligrams to 480 milligrams oftalsaclidine.

In one embodiment, cevimeline is used as the muscarinic Activator in themedicament. In another embodiment, the medicament contains from ninemilligrams to 750 milligrams of cevimeline. In a preferred embodiment,the medicament contains from 30 milligrams to 360 milligrams ofcevimeline.

In one embodiment, pilocarpine is used as the muscarinic Activator inthe medicament. In another embodiment, the medicament contains from 1.5milligrams to 500 milligrams of pilocarpine. In a preferred embodiment,the medicament contains from 10 milligrams to 200 milligrams ofpilocarpine.

In one embodiment, trospium chloride is used as the muscarinic Inhibitorin the medicament. In another embodiment, the medicament contains fromone milligram to 400 milligrams of trospium chloride. In a preferredembodiment, the medicament contains from 6.5 milligrams to 200milligrams of trospium chloride.

In one embodiment, trospium chloride extended release is used as themuscarinic Inhibitor in the medicament. In another embodiment, themedicament contains from one milligram to 400 milligrams of trospiumchloride extended release. In a preferred embodiment, the medicamentcontains from 6.5 milligrams to 200 milligrams of trospium chlorideextended release.

In one embodiment, solifenacin is used as the muscarinic Inhibitor inthe medicament. In another embodiment, the medicament contains from 0.25milligram to 100 milligrams of solifenacin. In a preferred embodiment,the medicament contains from 1 milligrams to 30 milligrams ofsolifenacin.

In one embodiment, tolterodine is used as the muscarinic Inhibitor inthe medicament. In another embodiment, the medicament contains from 0.2milligrams to 16 milligrams of tolterodine. In a preferred embodiment,the medicament contains from 0.7 milligrams to eight milligrams oftolterodine.

In one embodiment, fesoterodine is used as the muscarinic Inhibitor inthe medicament. In another embodiment, the medicament contains from 0.4milligrams to 56 milligrams of fesoterodine. In a preferred embodiment,the medicament contains between one milligrams to 28 milligrams offesoterodine.

In one embodiment, darifenacin is used as the muscarinic Inhibitor inthe medicament. In another embodiment, the medicament contains from n0.8 milligrams to 150 milligrams of darifenacin. In a preferredembodiment, the medicament contains from 2.5 milligrams to 30 milligramsof darifenacin.

While the subject is being treated, the health of the patient may bemonitored by measuring one or more of the relevant indices atpredetermined times during the treatment period. Treatment, includingcomposition, amounts, times of administration and formulation, may beoptimized according to the results of such monitoring. The patient maybe periodically reevaluated to determine the extent of improvement bymeasuring the same parameters. Adjustments to the amount(s) of subjectcomposition administered and possibly to the time of administration maybe made based on these reevaluations.

Treatment may be initiated with smaller dosages that are less than theoptimum dose of the compound. Thereafter, the dosage may be increased bysmall increments until the optimum balance between therapeutic effectand side effects is attained. This principle of drug titration is wellunderstood by those of skill in the art.

The medicament may also include one or more pharmaceutically-acceptablesalts. The medicament may include one or morepharmaceutically-acceptable carriers. The medicament may be administeredorally. The medicament may be delivered orally using tablets, troches,liquids, emulsions, suspensions, drops, capsules, caplets or gel capsand other methods of oral administration known to one skilled in theart. The medicament may also be administered parentally. Other routes ofadministration include but are not limited to: topical, transdermal,nasal, rectal, ocular, sublingual, inhalation, and vaginal. For topicaland transdermal administration, the medicament may be delivered in acream, gel, ointment, spray, suspension, emulsion, foam, or patch or byother methods known to one skilled in the art. For nasal administration,the medicament may be delivered by sprays, drops, emulsions, foams,creams, or ointments or by other methods known to one skilled in theart. For nasal administration, formulations for inhalation may beprepared as an aerosol, either a solution aerosol in which the activeagent is solubilized in a carrier, such as a propellant, or a dispersionaerosol, in which the active agent is suspended or dispersed throughouta carrier and an optional solvent. For rectal administration, themedicament may be delivered using suppositories, enemas, creams, foams,gels, or ointments or by other methods known to one skilled in the art.For ocular administration, the medicament may be delivered in drops,sprays, injections, solutions, emulsions, suspensions, or ointments, orby other methods known to one skilled in the art. For sublingualadministration, the medicament may be delivered in tablets, troches,liquids, emulsions, suspensions, drops, capsules, caplets or gel capsand by other methods of oral administration known to one skilled in theart. For administration by inhalation, the medicament may be deliveredin vapor, mist, powder, aerosol, or nebulized form, or by other methodsknown to one skilled in the art. For vaginal administration, themedicament may be delivered in solutions, emulsions, suspensions,ointments, gels, foams, or vaginal rings or by other methods known toone skilled in the art.

The medicament may be in a dosage form that immediately releases thedrug. In an alternative embodiment, the medicament may have a controlledrelease dosage form. In one embodiment, the medicament is packaged inliposomes. In a further embodiment, the liposome comprises aphospholipid. In a further embodiment, the phospholipid in the liposomeis selected from phosphatidylcholine (PC), phosphatidylglycerol (PG),phosphatidylinositol (PI), phosphatidylserine (PS),phosphatidylethanolamine (PE), phosphatidic acid (PA), eggphosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), eggphosphatidylinositol (EPI), egg phosphatidylserine (EPS), eggphosphatidylethanolamine (EPE), egg phosphatidic acid (EPA), soyphosphatidylcholine (SPC), soy phosphatidylglycerol (SPG), soyphosphatidylserine (SPS), soy phosphatidylinositol (SPI), soyphosphatidylethanolamine (SPE), soy phosphatidic acid (SPA),hydrogenated egg phosphatidylcholine (HEPC), hydrogenated soyphosphatidylcholine (HSPC), dipalmitoylphosphatidylcholine (DPPC),dioleoylphosphatidylcholine (DOPC), dimyristoylphosphatidylcholine(DMPC), dimyristoylphosphatidylglycerol (DMPG),dipalmitoylphosphatidylglycerol (DPPG), distearoylphosphatidylcholine(DSPQ), distearoylphosphatidylglycerol (DSPG),dioleoylphosphatidyl-ethanolamine (DOPE),palmitoylstearoylphosphatidyl-choline (PSPC),palmitoylstearolphosphatidylglycerol (PSPG),mono-oleoyl-phosphatidylethanolarnine (MOPE), dilauroylethylphosphocholine (DLEP), dimyristoyl ethylphosphocholine (DMEP),dipalmitoyl ethylphosphocholine (DPEP), distearoyl ethylphosphocholine(DSEP), dimyristoylphosphatidic acid (DMPA), dipalmitoylphosphatidicacid (DPPA), distearoylphosphatidic acid (DSPA),dimyristoylphosphatidylinositol (DMPI), dipalmitoylphosphatidylinositol(DPPI), distearoylphosphatidylinositol (DSPI),dimyristoylphosphatidylserine (DMPS), dipalmitoylphosphatidylserine(DPPS), distearoylphosphatidylserine (DSPS), N-acylatedphosphorylethanolamine (NAPE), and combinations thereof.

In a further embodiment, the controlled release formulation comprises asemi-permeable membrane. The muscarinic Activator and muscarinicInhibitor may be in different membranes in the same formulation. Inanother embodiment, the muscarinic Activator and muscarinic Inhibitorcan be in different membranes in different formulations or dosingvehicles. In a further embodiment, the semi-permeable membrane comprisesa polymer. In a further embodiment, the controlled release formulationcomprises a matrix that suspends the muscarinic Activator(s) andInhibitor(s). The muscarinic Activator and Inhibitor may be in separatematrices within the same medicament. In a further embodiment, the matrixcomprises a polymer. In a further embodiment, the polymer comprises awater soluble polymer. In a further embodiment, the water solublepolymer is selected from Eudragit RL, polyvinyl alcohol,polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, polyethylene glycol, and mixturesthereof. In a further embodiment, the polymer comprises a waterinsoluble polymer. In a further embodiment, the water insoluble polymeris selected from Eudragit RS, ethylcellulose, cellulose acetate,cellulose propionate, cellulose acetate propionate, cellulose acetatebutyrate, cellulose acetate phthalate, cellulose triacetate, poly(methylmethacrylate), poly(ethyl methacrylate), poly(butyl methacrylate),poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecylmethacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate),poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutylacrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) lowdensity, poly(ethylene) high density, poly(propylene), poly(ethyleneterephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate),poly(vinyl chloride), polyurethane, and a mixtures thereof. In a furtherembodiment, the matrix comprises a fatty compound. In a furtherembodiment, the fatty compound is a wax or glyceryl tristearate. In afurther embodiment, the polymer comprises a water soluble polymer and awater insoluble polymer. In a further embodiment, the matrix furthercomprises a fatty compound.

The medicament may be in dosage forms that use other methods ofcontrolled release formulation known to one in the art (for example,Dixit & Puthli. J. Control Release. 2:94. 2009; Mizrahi & Domb. RecentPat Drug Deliv Formul. 2:108. 2008; Forqueri & Singh. Recent Pat DrugDeliv Formul. 3:40. 2009; Kalantzi et al. Recent Pat Drug Deliv Formul.3:49. 2009; Iconomopoulou et al. Recent Pat Drug Deliv Formul. 2:94.2008; Panos et al. Curr Drug Discov Technol. 5: 333. 2008;. Wan et al.Nanomed. 2:483. 2007. Wang et al. Drug Delivery: Principles &Applications. Wiley 2005).

In another embodiment, the medicament is used in combination with one ormore therapies that can include both psychotherapy and drugs.Therapeutic agents include but are not limited to antipsychotics,anxiolytics, anti-depressants, sedatives, tranquilizers and otherpharmacological interventions known to one skilled in the art. Atherapeutic agent may fall under the category of more than one type ofdrug. For instance benzodiazepines can be considered anxiolytics,sedatives and tranquilizers.

The above-described benefits of the novel methods and compositions ofthe present invention are illustrated by the non-limiting examples thatfollow.

EXAMPLES Example 1

In one example, the invention is a single capsule formulation containing75 milligrams of xanomeline and 20 milligrams of trospium chloride. Thecapsule consists of a gelatin shell surrounding a fill material composedof the active compounds, a vehicle, a surfactant and a modifier. Thevehicle is polyethylene glycol with a molecular weight in the range offrom 500 to 10,000 Daltons and is 10% of the fill material by weight.The surfactant is polysorbate 80 and represents 0.1% by weight of thefill material. The modifier is fumed silica present at 0.25% by weightof the fill material. The total fill material represents 50% of thetotal capsule weight and the gelatin shell is 50% of the total capsuleweight.

Example 2

A second formulation is the capsule in Example 1 with an additionalouter controlled release layer comprising an enteric material (materialthat is relatively insoluble in the acidic environment of the stomach).There are a variety of enteric materials known to one skilled in theart. For this specific formulation we use hydroxyethylcellulose whichwould compose 20% of total capsule weight.

Example 3

A third example is a formulation prepared as in Example 2, with thecapsule containing 225 mg of xanomeline and 60 milligrams of trospiumchloride.

Example 4

In one example, the invention is a single capsule formulation containing75 milligrams of xanomeline and 5 milligrams of solifenacin. The capsuleconsists of a gelatin shell surrounding a fill material composed of theactive compounds, a vehicle, a surfactant and a modifier. The vehicle ispolyethylene glycol with a molecular weight in the range of from 500 to10,000 Daltons and is 10% of the fill material by weight. The surfactantis polysorbate 80 and represents 0.1% by weight of the fill material.The modifier is fumed silica present at 0.25% by weight of the fillmaterial. The total fill material represents 50% of the total capsuleweight and the gelatin shell is 50% of the total capsule weight.

Example 5

A second formulation is the capsule in Example 41 with an additionalouter controlled release layer comprising an enteric material (materialthat is relatively insoluble in the acidic environment of the stomach).There are a variety of enteric materials known to one skilled in theart. For this specific formulation we use hydroxyethylcellulose whichwould compose 20% of total capsule weight.

Example 6

A third example is a formulation prepared as in Example 52, with thecapsule containing 225 mg of xanomeline and 10 milligrams ofsolifenacin.

References

All publications and patents mentioned herein are hereby incorporated byreference in their entirety as if each individual publication or patentwas specifically and individually incorporated by reference. In case ofconflict, the present application, including any definitions herein,will control.

Equivalents

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification. The full scope of the inventionshould be determined by reference to the claims, along with their fullscope of equivalents, and the specification, along with such variations.

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in this specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained by the present invention.

1.-31. (canceled)
 32. A method of treating a central nervous systemdisorder comprising administering to a patient a muscarinic Activatorwith a muscarinic Inhibitor where the central nervous system disorder isselected from the following: schizophrenia, Disorders Related ToSchizophrenia, Muscarinic Disorder, Movement Disorder, Mood Disorder,Cognitive Disorder, Attention Disorder, and Addictive Disorder.
 33. Themethod of claim 32, wherein the combination of the muscarinic Activatorand the muscarinic Inhibitor has a theta score of greater than
 230. 34.The method of claim 32, wherein the muscarinic Inhibitor and themuscarinic Activator are administered simultaneously.
 35. The method ofclaim 32, wherein from 1 milligram to 1 gram of the muscarinic Activatoris administered.
 36. The method of claim 32, wherein from 1 milligram to1 gram of the muscarinic Inhibitor is administered.
 37. The method ofclaim 32, wherein the muscarinic Activator and the muscarinic Inhibitorare packaged in one dosage vehicle.
 38. The method of claim 32, whereinthe muscarinic Activator and the muscarinic Inhibitor are formulated inan immediate release formulation.
 39. The method of claim 32, whereinthe muscarinic Activator and the muscarinic Inhibitor are formulated ina controlled release formulation.
 40. The method of claim 32, whereinthe muscarinic Activator and the muscarinic Inhibitor are administeredin combination with a therapeutic agent.
 41. The method of claim 40,wherein the therapeutic agent is selected from an antipsychotic, ananxiolytic, an anti-depressant, a sedative, a tranquilizer, andcombinations thereof.
 42. A medicament comprising a muscarinicActivator, a muscarinic Inhibitor, and a pharmaceutically acceptablecarrier.
 43. The medicament of claim 42, wherein the combination of themuscarinic Activator and the muscarinic Inhibitor has a theta score ofgreater than
 230. 44. The medicament of claim 42, comprising from 1 gramto 1 gram of the muscarinic Activator.
 45. The medicament of claim 42,comprising from 1 milligram to 1 gram of the muscarinic Inhibitor. 46.The medicament of claim 42, which is in the form of a tablet, troche,liquid, emulsion, suspension, drops, capsule, gel cap, cream, gel,ointment, foam, cream, aerosol, suppository, enema, or vaginal ring. 47.The medicament of claim 42, which is formulated as an immediate releaseformulation.
 48. The medicament of claim 42, which is formulated as acontrolled release formulation.